Volume 7, Issue 2, 2025

Our Associate Editor, Laurent Sheybani, discusses some very old and very recent findings on sleep physiology and function, hoping to raise further interest and publications in the field.

This scientific commentary refers to ‘Integrating genome-wide association studies and transcriptomics prioritizes drug targets for meningioma’, by Liao et al. (https://doi.org/10.1093/braincomms/fcaf053).

This scientific commentary refers to ‘Edonerpic maleate enhances functional recovery from spinal cord injury with cortical reorganization in non-human primates’, by Uramaru et al. (https://doi.org/10.1093/braincomms/fcaf036).

This scientific commentary refers to ‘Fatigue in early multiple sclerosis: MRI metrics of neuroinflammation, relapse and neurodegeneration’, by Meijboom et al. (https://doi.org/10.1093/braincomms/fcae278).

This scientific commentary refers to ‘Seizures and premature death in mice with targeted Kv1.1 deficiency in corticolimbic circuits’, by Paulhus and Glasscock (https://doi.org/10.1093/braincomms/fcae444).

Abanto et al. reported that the lower the cerebrospinal amyloid-β42 (Aβ42) levels, the worse the neuropsychiatric symptoms in patients with Alzheimer's disease who participated in anti-amyloid clinical trials. This suggests that strategies designed to increase Aβ42 levels could be beneficial in these patients.

Eagle et al. report that peripheral glial fibrillary acidic protein was inversely associated with odds of depression (but not suicidal ideation) within the first year of recovery in a cohort of >1500 adults with traumatic brain injury and negative head computed tomography scan at emergency department presentation.

Moresco et al. report that circulating cell-free mitochondrial DNA levels are significantly elevated in the cerebrospinal fluid of narcolepsy type 1 patients compared with controls. These levels negatively correlate with cerebrospinal fluid hypocretin-1 concentrations and are associated with sleep architecture alterations. Cytokine profiling suggests a neuroinflammatory process, implying a potential mitochondrial involvement.

Bag et al. report that medulloblastoma patients exhibit increased diffusivity and decreased fractional anisotropy in most cerebrum regions, along with cortical thinning in targeted areas, before undergoing any adjuvant therapy. These extensive microstructural changes suggest that cerebellar damage undermines the integrity of both cerebral grey and white matter.

Prevalence of enlarged cavum septum pellucidum was assessed on MRI as well as clinical correlates. Enlarged cavum septum pellucidum was seen more often in individuals exposed to repetitive head impacts compared with groups with a neurodegenerative disease or normal cognition, but not compared with individuals with traumatic brain injury. For those with repetitive head impacts, enlarged cavum septum pellucidum was associated with worse memory performance.

In this cross-sectional study of 84 hippocampal sclerosis patients and 43 healthy controls, Fiore et al. linked verbal learning variability to cortical and hippocampal morphometry. Smaller volumes in prefrontal, temporal, cingulate cortices and left dentate gyrus, CA4 and CA3 were associated with poorer verbal learning in temporal lobe epilepsy.

Liao et al. prioritized novel drug targets (XBP1, TTC28 and TRPC6) for meningioma by integrating genome-wide association studies and transcriptomics, with RNA sequencing and molecular docking validating them and revealing expressive characteristics, advancing understanding of meningioma’s molecular landscape.

See Bertero, Padovan and Lombardi (https://doi.org/10.1093/braincomms/fcaf088) for a scientific commentary on this article.

Alanko et al. showed that a multiplex panel of brain-derived proteins in the CSF reflects biological heterogeneity in a real-world memory clinic cohort. The biosignatures were associated with the Alzheimer’s disease CSF biomarker profiles of ATN (amyloid, phosphorylated tau and neurodegeneration pathology), yet only to a small extent with clinical diagnosis, cognition and imaging biomarkers.

Koirala et al. report how neural underpinnings of the reading network are mediated in children with cochlear implants, highlighting the importance of intervention timing and duration of deafness. Their study shows early auditory deprivation poses persistent challenges to optimal reading development, underscoring the need for specialized support.

Sun et al. analysed plasma biomarkers in a Chinese cohort to diagnose Alzheimer’s disease and distinguish it from other dementias. Phosphorylated tau protein at threonine 181 effectively identified patients with Alzheimer’s disease, while the amyloid-beta 42 to phosphorylated tau 181 ratio showed potential for tracking disease progression.

Uramaru et al. revealed the efficacy of edonerpic maleate on grasping movement after cervical spinal cord injury and the change of cortical motor representation with intracortical microstimulation in non-human primates. They proposed that edonerpic maleate could be a therapeutic alternative for paralysis after spinal cord injury.

See Machado and Hollis (https://doi.org/10.1093/braincomms/fcaf076) for a scientific commentary on this article.

Savarit et al. studied the relationship between brachial plexus anaesthesia (BPA), and sensations and changes in joint, and position sense in the upper limb. They conclude that phantom limb sensations and altered proprioception appear rapidly following BPA, inducing a chemical deafferentation of the upper limb.

Beber et al. investigate the neurofunctional correlates of sentence comprehension in individuals with aphasia. Results link pre-frontal regions to local morphosyntactic processes (e.g. noun–verb agreement) and temporo-parietal regions to establishing who does what to whom, with parietal regions being critical for processing sentences with non-canonical word order (e.g. passives).

Hadaya et al. parsed brain–behaviour heterogeneity in adults subdivided according to their clinical birth status (very preterm versus full term) and/or data-driven behavioural phenotype (regardless of birth status). They identified alterations in resting state functional connectivity associated with very preterm birth that differed from those underlying less favourable behavioural outcomes.

Lindzon et al. reported a novel zebrafish mtmr5/sbf1 knockout model of Charcot-Marie-Tooth type 4B3 that recapitulates key features of the human disorder and provides a first in vivo model for therapy development.

Fatigue is a major cause of disability after traumatic brain injury. Anliker et al. studied the neural correlates using EEG, finding disrupted resting-state alpha-band connectivity and reduced brain activation during tasks in fatigued patients. These findings may suggest new therapeutic targets.

Cao et al. report the properties of network dynamic reconfiguration in world class gymnasts by using a multilayer network analysis and found decreased flexibility across multiple scales compared with non-athlete controls. This result suggests that long-term intensive training may promote a more stable and efficient brain functional configuration.

The study examined brain responses to natural speech, i.e. neural tracking, in post-stroke aphasia. Individuals with aphasia exhibited reduced neural tracking of speech compared to healthy controls. Furthermore, neural tracking emerged as an accurate, sensitive, reliable and time-efficient marker for capturing aphasia at the individual level.

Scotton et al. report distinct subtypes of atrophy progression in corticobasal syndrome identified using machine learning analysis of structural MRI scans. These subtypes correlate with underlying pathologies, such as primary tauopathies and Alzheimer's disease, with important implications for screening on entry into clinical trials, and tracking disease progression.

Connectivity within the theta and alpha bands is reduced in boys with autism, according to Barnes et al. Their phase-based functional and effective connectivity analyses of EEG data are robust against amplitude perturbations through movement artefacts and noise. It promises reliable clinical evaluation of children with autism, even during movement.

In Alzheimer's disease, pathological tau processing is characterized by post-translational changes such as hyperphosphorylation and truncation. TG3 correlates with cognitive impairment and is present in pre-Neurofibrillary tangle. This epitope was very stable to proteolytic processing by caspases. The entorhinal cortex showed high sensitivity to pathological tau processing.

Li et al. explored the potential neural mechanisms of repetitive transcranial magnetic stimulation over the left dorsolateral prefrontal cortex for smoking cessation. They reported that repetitive transcranial magnetic stimulation may work by reducing cerebral blood flow in the target region and increasing functional connectivity with fronto-striatal pathways.

Gong et al. reported NEFL and RPS6KB1 as robustly associated with all-cause dementia, MMP12 with vascular dementia in the English Longitudinal Study of Ageing. Validation in UK Biobank confirmed these findings. Combining biomarkers with predictors achieved high predictive accuracy. Machine learning and Mendelian randomization highlight potential early markers and mechanisms.

Tremblay et al. report similar, but less severe, pattern of atrophy progression in the brain of individuals with a family history of Alzheimer’s disease and Alzheimer's disease. This pattern follows brain connections and is related to the accumulation of two proteins implicated in Alzheimer's disease pathology, tau and beta-amyloid.

Nassan et al. leveraged Mendelian randomization to evaluate whether genetically predicted brain connectivity patterns can influence the risk for neurodegeneration later in life. Although the results overall did not support this hypothesis, they report a possible association between the visual network connectivity and Lewy body disease, which requires further study.

Lindblad et al. utilized antibody arrays to quantify 101 proteins in cerebral microdialysate longitudinally following human severe traumatic brain injury among 26 patients with different apolipoprotein E genotypes. They delineate time, age and apolipoprotein E genotype-dependency for brain extracellular protein levels, and present two novel candidates for future pathophysiological studies.

Among individuals diagnosed with Parkinson disease with pathogenic variants in the LRRK2 gene, compared with those with CSF alpha-synuclein aggregates, those without evidence of aggregated alpha-synuclein have higher putamenal dopamine transporter binding and exhibit less severe motor manifestations and decline over up to 4 years.

Individuals with drug-resistant epilepsy may suffer from cognitive decline. Akel et al. examined levels of blood–brain injury biomarkers in epilepsy, with a focus on drug-resistance. They found higher levels of neurofilament light and glial fibrillary acidic protein in drug-resistant epilepsy. Neurofilament light remained significantly increased even after excluding patients with brain lesions.

Epilepsy is a cortico-subcortical network disorder. By analysing thalamo-cortical relationships in 121 patients through stereotactic-EEG, Biagioni et al. identified that higher thalamic hyperexcitability and strength functional connectivity during sleep correlates with worse surgical outcomes, while changes in thalamic strength functional connectivity during rest recordings offer insights into epilepsy duration and age effects.

Haas et al. compared the brain volumes of Moyamoya patients with those of healthy individuals. They revealed a previously undocumented percentage difference of brain atrophy depending on the severity of the disease, showing that Moyamoya can affect the entire brain even without a manifest stroke.

Adegboro et al. report increased grey matter volume, fractal dimension, and cortical thickness in key frontal regions of vestibular schwannoma patients after adjusting for age, sex, hearing loss and tinnitus. These findings contribute to a more nuanced understanding of the tumour and highlight potential targets for non-invasive management.

Chang et al. report that appetite loss is more prevalent in patients with Motor Neuron Disease than in controls and contributes to weight loss due to fat mass loss. Functional MRI reveals altered activity in the temporal pole and cerebellum, implicating brain regions not conventionally involved in non-motor aspects of the disease.

Maria et al. explore explainability as a strategy to add specificity to brain age gap estimation (BrainAGE) as a putative biomarker. Three clinical conditions are compared: Type 2 diabetes, schizophrenia and Alzheimer’s disease. The results suggest that explainability could be a strategy to decode the disease behind an increased BrainAGE.

Essex et al. report that individualized quantitative susceptibility mapping reveals depth- and curvature-specific cortical iron abnormalities following mild traumatic brain injury. Elevated iron was evident primarily in the temporal lobe, and regional iron accumulation was associated with greater injury severity. These findings implicate cortical iron dysregulation in post-injury pathophysiology.

Bancroft et al. measured how intracranial pressure and pulsatility changed when the head moved from neutral into various positions whilst seated, standing or supine. Intracranial pressure and pulsatility increased in most but not all combinations of head and body position, and was often greater in patients with a shunt malfunction.

Low-intensity pulsed ultrasound alleviated dextran sulphate sodium-induced colonic and hippocampal inflammation through transcranial stimulation of mice. Transcranial LIPUS stimulation could be a novel therapeutic strategy for inflammatory bowel disease and neuroinflammation via regulation of inflammatory interactions across brain–gut axis signaling.

Gkotsoulias et al. assessed an unexplored facet of Tourette syndrome using 7 Tesla MRI and dopamine D₁ receptor–specific PET. Reductions in brain iron surrogates and post-synaptic D₁ receptor availability—also associated with motor tic severity—reveal an inter-play between iron homeostasis and dopaminergic abnormalities, shedding new light on the disorder's complex neurobiological underpinnings.

D’Gama et al. studied a prospective patient cohort being evaluated with stereo-EEG electrodes for seizure localization. They identified somatic mosaic variants by studying DNA retrieved from individual electrodes. These findings suggest the future potential to identify precise genetic diagnoses in the setting of minimally invasive recording.

Kremen et al. report that both continuous low-frequency and duty cycle high-frequency anterior nucleus of the thalamus deep brain stimulation (ANT-DBS) reduced seizures in five ambulatory subjects with temporal lobe epilepsy. However, low-frequency ANT-DBS showed greater reductions in interictal epileptiform spikes, electrographic seizures and better sleep and memory outcomes.

Adamo et al. investigate brain tissue properties and their associations with cognitive function in individuals with Down syndrome receiving pulsatile gonadotropin-releasing hormone therapy. Over 6 months, quantitative magnetic resonance imaging reveals stable differential patterns of neuronal loss and myelination in comparison with a healthy control group.

Huang et al. report that spinocerebellar ataxia type 3 (SCA3) patients exhibit increased perivascular space (PVS) burden in multiple brain regions compared with healthy controls, correlating with motor impairment. The PVS burden may serve as a novel imaging biomarker for SCA3 disease monitoring and a potential therapeutic target.

Yamada et al. used a deep learning model to automatically segment 3D T1-weighted MRI images into 100 detailed brain subregions and 7 CSF subregions, discovering that the volume ratios of the supramarginal gyrus and paracentral gyrus were smaller in patients with Hakim's disease (idiopathic normal-pressure hydrocephalus) compared to healthy controls.

Yang et al. found suboptimal brain network organization and a subnetwork with low network connection in systemic lupus erythematosus patients using functional MRI. Functional MRI-based network analysis and support vector machine can identify systemic lupus erythematosus-related brain function abnormalities.

Almeida e Sousa et al. report that although there is no direct genetic correlation between Alzheimer’s disease and schizophrenia, both disorders are genetically correlated with loneliness and the genetic overlap that underpins socioeconomic-related risk factors. This study helps to refine our knowledge of the pleiotropic pathways between schizophrenia and dementia.

Tomlinson et al. examined dynamic patterns of interictal epileptiform discharges in children with refractory epilepsy, finding that synchronous discharges arise preferentially in seizure onset nodes and propagate through networks of functionally connected brain regions.

In this observational study, Wu et al. report the finding of temporal lobe dysfunction in pain-depression comorbidity among PHN patients by using functional MRI. This result may offer heuristic cues for central therapeutic targets that could disrupt the pain-depression vicious circle.

Tandon et al. report that machine learning analysis of cerebrospinal fluid proteins identifies eight peptides that discriminate between healthy controls and Alzheimer’s disease patients. These peptides effectively stratify cognitively normal individuals with underlying pathology into subgroups showing concordance with disease progression markers across two independent cohorts.

Yasmin, Marwick et al. report that GluN2A N-methyl-D-aspartate receptor subunit absence in CA1 pyramidal neurons leads to a decrease in the frequency of excitatory miniature synaptic currents and decreased density of proximal dendrites. Nevertheless, loss of this N-methyl-D-aspartate receptor subunit does not impact excitatory postsynaptic potential summation or synaptically-evoked action potential firing.

Voysey et al. studied sleep in Huntington's disease gene carriers in a 12-year longitudinal study using polysomnography and actigraphy. They found that sleep abnormalities emerge many years prior to motor features, may form a predictive biomarker of disease onset and, importantly, are associated with greater cognitive deficits and disease activity.

α-Synuclein aggregation, central to neurodegenerative disorders like Parkinson’s disease and dementia with Lewy bodies, involves transitions to β-sheet-rich structures forming aggregates. Coles et al. used Raman spectroscopy and machine learning to analyse α-synuclein aggregation and lipid alterations, revealing reductions in sphingomyelin and increases in ceramide, consistent with oxidative stress and apoptosis.

Basgaran et al. reported that in countries with a high incidence of Alzheimer’s disease, the composition of the gut microbiome significantly differs, with lower diversity (P < 0.05). Using machine learning, they successfully predicted the population incidence of Alzheimer’s disease based on gut microbiome profile.

Retrospective data analysis of 99 patients with amyotrophic lateral sclerosis to evaluate prognostic biomarkers and modifiable factors related to cognition and behavioural abnormalities. The continued relevance of total tau in neurodegenerative diseases should be reemphasized. A surprising potential therapeutic target—A high normal thiamine level as a positive prognostic marker.

Using classical biochemical methods and mass spectroscopy, Becker et al. characterized aggregate forms of the neurofilament light protein in cerebrospinal fluid. Neurofilament light protein was found to be truncated, forming disulfide-linked complexes. Knowledge about these structures is of importance for the correct quantitation of neurofilament light protein in neurodegeneration biomarker assays.

Ranasinghe et al. reported changes in neural activity patterns of the brain in healthy older individuals ranging from 50 to 90 years. The authors identify specific changes that are compensatory and associated with better cognitive performance as well as those that are compromised and associated with poor cognitive performance.

Zhang et al. report that various markers of cerebral small vessel disease were highly prevalent among rural-dwelling Chinese older adults. Older age, hypertension, and coronary heart disease were the main factors associated with cerebral small vessel disease.

Spruyt et al. report that in asymptomatic Alzheimer’s disease higher tau PET load in medial temporal cortex is associated with decreasing global clustering coefficient and increasing characteristic path length; graph measures derived from high-density resting-state EEG. This marks the transitional phase between cognitively unimpaired amyloid negative and prodromal Alzheimer’s disease.

Karlsson et al. report that in 570 patients with migraine from a tertiary headache centre, chronic migraine, daily headache and multiple prior preventive drug failures were associated with reduced efficacy of erenumab—a calcitonin-gene related peptide-antagonist—while older age predicted better outcomes. Severe phenotypes were linked to delayed responses.

Flanagan et al. report functional connectivity, using ultra-high-field functional magnetic resonance imaging, during prospective remembering, between the anterior nuclei of the thalamus and cortical regions engaged in memory and attention networks. The findings suggest a coordinatory role for these nuclei.

Nakamura et al. report that the presence of chronic pain at baseline is associated with a significantly greater decrease in the volume of the postcentral gyrus, thalamus, anterior cingulate cortex, amygdala, right hippocampus and right insula 5 years after baseline in 766 community-dwelling older Japanese.

Microglia, the immune cells of the brain, are important in neurodegenerative disorders. They may also help spread diseased proteins within the brain, prion-like proteins. In this review, Öztürk et al. summarize the current knowledge on the role of microglia in prion-like transmission of proteins in the most common neurodegenerative diseases.

Ganos et al. present a taxonomy of ‘religious motor behaviours’, integrating concepts from movement disorders and cognitive neuroscience. This framework reveals several parallels between voluntary and involuntary religious actions and clinical motor phenomena, suggesting common neurocognitive pathways shaped by cultural contexts.

Abbott et al. describes Alzheimer’s disease pathology associated with neuroinflammation. Tregs are neuroprotective CD4+ T-cells that maintain central nervous system homeostasis by reducing inflammation and inhibiting T cell proliferation and cytokine production. They also reduce microglia-mediated inflammation, inhibit neurotoxicity, neuroinflammation and the progression of neurofibrillary tangles and Aβ production.

Scarcella et al. explore the role of multiomics in understanding amyotrophic lateral sclerosis, focusing on proteomics, metabolomics, lipidomics and microbiomics. They discuss how these approaches uncover pathogenic protein aggregation, metabolic alterations and microbial changes, which may lead to improved biomarkers, diagnosis and the development of targeted amyotrophic lateral sclerosis therapies.

Sassani et al. review the current and prospective roles of magnetic resonance imaging in mild traumatic brain injury (mTBI), elucidating mTBI pathophysiology and highlighting potential of MRI as a biomarker in mTBI.

Assogna et al. report the results of a Phase 2, randomized, double-blind, placebo-controlled trial in 48 patients with a diagnosis of probable frontotemporal dementia, showing that co-ultramicronized palmitoylethanolamide combined with luteoline exhibits encouraging efficacy in slowing down the progression of cognitive and functional symptoms.